Understanding the Role of Somatic Mutations in Adult Inflammatory Diseases - Inflammatory rheumatologic diseases affect millions of individuals and represent a significant public health
burden. Considerable progress has been made in understanding the molecular basis of rheumatic disease, but
molecular diagnoses and mechanistic insights into the causes of adult-onset disease are incomplete. In addition,
although there are many effective treatments, a significant percentage of patients remains poorly controlled on
current standard of care therapies. It is therefore crucial to improve our understanding of the molecular signaling
underlying these life-threatening diseases, which in turn will lead to more effective treatments. To date, a wealth
of genetic data has identified common polymorphisms associated with rheumatologic diseases, however very
few causative and targetable variants have been identified.
We have performed a genotype-first analysis looking for mutations in genes in the ubiquitin pathway in our cohort
of patients with undiagnosed inflammatory disorders and have identified affected individuals who share somatic,
missense mutations in the UBA1 gene at the same codon, p.Met41 (Beck DB et al, NEJM). All of these individuals
have overlapping disease manifestations, including fevers, pulmonary infiltrates, skin lesions, arthralgias,
peripheral blood counts concerning for hematologic malignancy, characteristic vacuolization of hematopoietic
precursor cells, and a failure to respond to any therapy other than high dose corticosteroids. We have named
this disease VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory Somatic) syndrome. Patients with
VEXAS syndrome meet clinical criteria for seemingly disparate inflammatory (relapsing polychondritis,
polyarteritis nodosa, giant cell arteritis) and hematologic (myelodysplastic syndrome or plasma cell dyscrasias)
conditions. UBA1 p.Met41 mutations are restricted to the myeloid lineage, primarily absent from lymphoid
lineages, and cause severe inflammatory disease. Furthermore, we have identified that mutations in UBA1 at
p.Met41 lead to altered protein isoform expression and translation of a toxic isoform. In the work proposed here,
I will study how mosaic mutations in myeloid cells result in aberrant myeloid and lymphoid lineage development
and inflammation at the cellular and molecular level (Aim 1). I will then characterize the prevalence and
penetrance of UBA1 mutations and find additional genetic causes of other late-onset inflammatory diagnoses
(Aim 2). Based on our current findings, I hypothesize that somatic variants are an overlooked cause of many
severe, adult-onset inflammatory diseases. Our results with VEXAS syndrome demonstrate that by analyzing
genetic variants in a broad spectrum of severe inflammatory diseases we can uncover common underlying
mechanisms of pathogenesis which may reveal clinically important reclassifications of disease and ultimately
lead to improved clinical care.